Vesicoureteral reflux (VUR) is a congenital disease, the incidence of which differs greatly according to race. It is reported that the incidence of VUR is observed in 10% or more of the fetuses of white people of U.S.A. and Europe, which is the highest level of incidence among all the races. Prognosis varies depending on a variety of factors such as the severity of VUR, complications with congenital renal hypoplasia, or occurrence of renal scars resulting from recurring urinary tract infection. When adequate medical treatment is not provided at an early stage, VUR often develops into renal dysfunction and then into renal failure at maturity. It has actually been reported that VUR is observed in approximately 20% of patients with advanced renal dysfunctions. The diagnosis of VUR requires voiding cystography that involves the insertion of a catheter into the urethra. Despite the seriousness of VUR, a simple diagnostic method that can be utilized for screening has not yet been established. Thus, almost every patient suspected of having VUR is required to undergo an invasive X-ray test under the present circumstances.
If VUR is diagnosed at an early stage, many patients who would eventually develop renal failure and have to receive long-term hemodialysis can be relieved by the provision of adequate medical treatment and management. This can result in conservation of medical resources on a global scale. Accordingly, development of a simple and non-invasive diagnostic method that can easily detect VUR in all newborn babies has been awaited.
Interstitial cystitis (IC) is a relatively common disease, to an extent that there are approximately 700,000 patients in U.S.A. (90% or more of the patients are females). The principal complaints of IC are a strong urgency of urination, an increased urinary frequency, and pain when the bladder is full. Although the severity thereof varies, the “quality of life” of the patients becomes significantly deteriorated. However, no effective therapeutic method has yet been developed. Diagnosis of IC has never been easy. It is a serious issue of concern that diagnosis of IC requires invasive tests, such as observation of mucosal petechial bleeding via cystoscopy and biopsy of bladder mucosa under anesthesia, in addition to a thorough inquiry and an urodynamics. Many factors, such as mechanical irritation, allergy, immune responses, neurovascular problems, or urinary tract infection, are considered to be associated with IC. However, there is no conclusive evidence regarding any such factors, and a simple and non-invasive method for diagnosing IC has not yet been developed.
Uroplakins (UPs) are membrane proteins that are expressed specifically in urothelial cells (of the mucous membrane of the urethra, the bladder, the ureter or the renal pelvis), and 4 types of constitutive proteins have been identified. They are the 27-kDa Ia (UPIa), the 28-kDa Ib (UPIb), the 15-kDa II (UPII), and the 47-kDa III (UPIII) types. These 4 types of protein families form plaques on the uppermost urothelial layer. The uroplakin family is considered to function to stabilize the urothelial surface or as a permeability barrier, although the detailed physiology thereof has not yet been elucidated. In the Japanese Journal of Cancer Research, 89: 879, 1998, cloning of the human UPIII gene was reported. In the Japanese Journal of Cancer Research, 93: 523, 2002, a polyclonal antibody specific for UPIa was reported, and the clinical utility thereof as a histological marker of urinary tract transitional epithelial carcinoma (bladder carcinoma, ureteral carcinoma, or renal pelvic carcinoma) was suggested.
In recent years, a report has been made in which a uroplakin III (UPIII) gene knockout mouse, which had been prenatally subjected to genetic engineering so as not to allow the target protein to express its functions, developed bilateral VUR (Journal of Cell Biology, 151: 961, 2000). In contrast, it was also reported that “gene mutation was not detected” as a result of UPIII gene analysis, which targeted patients with familial VUR (Journal of Urology, 171: 931-2, 2004). Accordingly, causes for VUR or IC have not yet been elucidated, and no screening method that can be employed has yet been known.